The action potentials measured by an extracellular electrode are the tip of a computational iceberg, beneath which operates a vast electrochemical signaling system involving fast neurotransmitters, neuromodulators, hormones, the receptors that bind these signaling molecules, and the intrinsic membrane properties of the neurons in which these receptors reside. Consequently, the extracellular electrodes commonly used to study neural activity in freely behaving animals are blind to a wide spectrum of brain activity. This insensitivity limits our understanding of the neural mechanisms underlying normal brain function and also limits insights into disordered neural activity that underlies neurological and neuropsychiatric diseases. Surmounting this limitation requires technology that can overcome the formidable challenge of obtaining intracellular recordings from neurons in the brain of a freely behaving animal. This proposal seeks to overcome this challenge by accomplishing three Specific Aims: 1) To develop a miniature microdrive in which the intracellular electrode can be rapidly loaded and flexibly positioned over the brain surface. 2) To miniaturize the size and mass of the drive so that a mouse can readily carry at least two devices, facilitating an assessment of functional connectivity between neurons and brain areas. 3) To make intracelular recordings in the auditory cortex of freely behaving mice as they process auditory stimuli in conditions that are known to strongly modulate auditory responses. The refinement of this technology will be widely beneficial to the neuroscience community and its application in the mouse will open the door to analyzing how disordered neural activity underlies diseases. ! PUBLIC HEALTH RELEVANCE: This proposal seeks to develop a miniature intracellular recording device that can be used to make highly sensitive recordings of neural activity in freely moving animals. Development of this technology can provide a powerful tool for elucidating neuronal activity that enables normal brain function and disordered neuronal activity underlying diseases. !